There is no permanent cure for connective diseases of the skin, such as cutaneous forms of Lupus Erythematosus. Today, the treatment of connective diseases includes topical treatment with strong steroids, sometimes in combination with anti-malarial drugs or systemic immuno-suppressants. Unfortunately, the treatment with such drug agents has serious side effects and cannot be applied for prolonged periods.
The present inventor has recognised the strong need for therapeutic agents that can effectively alleviate the symptoms of cutaneous forms of Lupus Erythematosus (LE) without exhibiting significant adverse effects. Quite surprising, the present inventor has found that the topical application of a beta2-adrenoceptor agonist effectively relieves the clinical manifestations in cutaneous forms of Lupus Erythematosus.
Cutaneous forms of Lupus Erythematosus (Cutaneous Lupus Erythematosus) encompass at least 10 to 15 different clinical presentations that usually can be divided into 3 categories, including (1) acute cutaneous lupus erythematosus (ACLE), (2) subacute cutaneous lupus erythematosus (SCLE), and (3) chronic cutaneous lupus erythematosus (CCLE). Some of the common types of cutaneous LE include chronic cutaneous lupus erythematosus (CCLE) and various sub-types thereof.
Current evidence indicates that cutaneous Lupus Erythematosus is a separate disease from systemic Lupus Erythematosus and not just a benign variant of systemic LE in that the two diseases seems to be genetically different diseases (Rook's, Textbook of Dermatology, chapter 65, page 56.2, volume 3, 7th edition, edited by Tony Burns et al, Blackwell Science, 2004). Systemic Lupus Erythematosus (SLE) is the most common connective tissue disease and is characterised by multi-organ inflammation, which most commonly affects the skin, joints and vasculature. Almost any organ or system of the body, including the lungs, kidneys, heart or brain may be affected by the inflammation.
Beta2-adreneroceptor agonists are traditionally used in the treatment of respiratory diseases such as asthma, chronic bronchitis and nervous system injury. Beta2-adrenoceptor agonists has also been found to interact with specific receptors on T-lymphocytes to mediate anti-inflammatory activities (Baramki D et al. Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer. J Allergy Clin Immunol 2002 March; 109(3):449-54) and Barnes P J. Effect of beta-agonists on inflammatory cells. J Allergy Clin Immunol 1999 August; 104(2 Pt 2):S10-S1)7.
A number of drug agents and combinations thereof have been proposed for the treatment of various inflammatory diseases including discoid Lupus Erythematosus, wherein a beta2-adrenoceptor agonist among other drug agents is proposed to be administered as a secondary active drug agent.
The patent application US2005192261 relates to topical treatment with combinations of an antihistamine or an antihistamine analogue and a corticosteroid.
The patent application WO05051293 relates to topical treatment with Ibudilast or a related compound.
The patent application US2004220153 relates to topical treatment with a selective serotonin reuptake inhibitors (SSRI).
The patent application US2004224876 relates to topical treatment with a non-steroidal immunophilin-dependent immunosuppressant (NsIDI) and an NsIDI enhancer (NsIDIE).
Notably, none of the above-mentioned patent application relates to the direct treatment of cutaneous forms of LE with a beta2-adrenoceptor agonist, neither as the sole therapeutically agent nor as the primary therapeutically agent.
Furthermore, a number of treatment regimens have been proposed for the treatment of systemic LE. In these treatments, the primary therapeutically effective drug agent eventually may be co-administered with a beta2-adrenoceptor agonist:
The patent application WO2003092617 relates to the treatment of an inflammatory skin disease, such as systemic Lupus Erythematosus, by topically administering a steroid and a beta-adrenergic receptor ligand.
The patent application US2003236298A1 (Atherogenics Pharmaceuticals, Inc) relates to 1,3-bis-(substituted-phenyl)-2-propen-1-ones that are inhibitors of the expression of VCAM-1 for the treatment of patients with a disease mediated by VCAM-1, such as systemic Lupus Erythematosus.
The patent applications US2005130935 and WO 2003097073 (Astion Development A/S) relate to combinations of a beta2-adrenoceptor agonist and an aminosugar for the treatment of inflammatory diseases, including systemic Lupus Erythematosus.
The patent applications US20050176714 and WO2003104204 relate to pyridazine derivatives acting as phosphodiesterase IV inhibitors for the treatment of autoimmune diseases, such as systemic Lupus Erythematosus.
Furthermore, unusual respiratory manifestations of systemic Lupus Erythematosus, “shrinking lungs” have been treated with albuterol (Salbutamol) (Thompson P J, Dhillon D P, Ledingham J, Turner-Warwick M. Shrinking lungs, diaphragmatic dysfunction, and systemic Lupus Erythematosus. Am Rev Respir Dis. 132(4), 926-8, 1985).
Topical administration of beta2-adrenoceptor agonists has been shown to result in sensitization of the skin and allergic reactions. For example, salbutamol (albuterol) has been reported to be a topical sensitizer that causes contact dermatitis reactions when applied to the surface of the skin of humans (in Biochemical Modulation of Skin Reactions, page 10-11, edited by Agis K. Kydonieus and John J. Wille, CRC Press LCC 2000).
However, the present inventor has overcome this problem by providing topically administrable compositions only or mainly comprising the R-enantiomeric form of a beta2-adrenoceptor agonist.
Topically administrable compositions comprising an enantiomerically pure beta2-adrenoceptor agonist have been disclosed in the art:
The patent application US2005192261 discloses topical compositions primarily comprising an antihistamine or an antihistamine analogue and a corticosteroid.
The patent application WO05051293 (COMBINATORX, INCORPORATED) discloses topical compositions primarily comprising Ibudilast or related compounds.
The patent application US2004220153 discloses topical compositions primarily comprising selective serotonin reuptake inhibitors (SSRI).
The patent application US2004224876 discloses topical compositions primarily comprising a non-steroidal immunophilin-dependent immunosuppressant (NsIDI) and an NsIDI enhancer (NsIDIE).
The patent application WO2003092617 (COMBINATORX, INCORPORATED) discloses topical compositions comprising a steroid and a beta-adrenergic receptor ligand.
Topical compositions of a beta2-adrenoceptor agonist are proposed in several documents, but these fail to emphasise the importance of administering the enantiomeric pure form: The patent application U.S. Pat. No. 4,574,129 (Bristol-Myers Company) discloses topical compositions comprising a beta2-adrenoceptor agonist and vehicle materials for the treatment of topical anti-inflammatory effect in mammals.
The U.S. Pat. No. 4,699,777 (Schering Corporation) discloses transdermal compositions of albuterol further comprising 5 to 50% of 1-dodecyl-azacycloheptan-2-one and 5 to 50% of non-aqueous urea.
The U.S. Pat. No. 4,975,466 (Ciba-Geigy Corporation) discloses topical compositions based on Formoterol and related compounds for use in the treatment of inflammatory skin diseases.
The U.S. Pat. No. 4,980,159 (Bristol-Myers Squibb Company) discloses post-shave compositions (aqueous solutions) comprising a beta2-adrenoceptor agonist for pilomotor effects.
The U.S. Pat. No. 6,267,972 (Societe L'Oreal S. A) discloses cosmetic/pharmaceutical compositions for the treatment of cutaneous diseases and sensitive skin comprising an effective substance P antagonist amount of at least one beta2-adrenoceptor agonist together with an skin irritant.
The patent application WO05102296 (HEPTAGEN LIMITED) discloses topical compositions comprising a combination of vitamin D or an analogue, preform or derivative thereof, a cannabinoid or cannabinoid receptor agonist, and a beta2-adrenoceptor agonist for the treatment of psoriasis.
The patent application WO03088997 (UNIVERSITEIT UTRECHT HOLDING B.V) discloses topical compositions of an antigen and a beta2-adrenoceptor agonist for the induction of tolerance to treat autoimmune diseases, delayed type hypersensitivity reactions and/or transplant rejection, and/or graft versus host reaction and/or allergic reactions.
The patent application US2003236298A1 (Atherogenics Pharmaceuticals, Inc) discloses topical compositions of 1,3-bis-(substituted-phenyl)-2-propen-1-ones inhibiting the expression of VCAM-1.
The patent application US2005130935A1 (Astion Development A/S) discloses combinations of beta2-adrenoceptor agonist and an aminosugar for the treatment of inflammatory diseases.
The patent application JP7304647 (KAO CORP) discloses compositions for massage comprising one or more compounds selected from (A): (i) a xanthine derivative, (ii) a beta-adrenergic agent, (iii) an alpha-2 adrenergic activity inhibitor, and (iv) a bipyridine derivative; and (B) a scrubbing agent.
The patent application JP9110674 (KAO CORP) discloses a bathing composition comprising a compound of the plant of pepper family (e.g. Piper nigrum L, Piper longum L, Piper angustifolium), carbonate and an organic acid.
The patent application JP 61-154201(TEIJIN LTD) discloses transdermal compositions comprising a β-stimulation agent and a dissolution assistant agent.
The patent application JP 06-048497 (Kao Corp) discloses a bathing agent composition containing a β-adrenergic stimulant, inorganic salt, an organic acid and an oily component.
The patent application U.S. Pat. No. 4,088,756 (The Regents of the University of Michigan) relates to topically applied compositions comprising at least one active compound selected from the groups α1, β1, and β2-adrenergic agents and oral hypoglycemic agents.
The patent application WO05102296A2 (HEPTAGEN LIMITED) relates to topically applied compositions comprising vitamin D or its analogue, cannabinoid or a cannabinoid receptor agonist; and a beta-adrenoceptor agonist for the treatment of immuno-proliferative skin diseases.
The patent application WO2003092617 (COMBINATORX, INCORPORATED) relates to topically applied compositions comprising a steroid and a beta-adrenergic receptor agonist for the treatment of an inflammatory skin disease.
The patent application WO9519336 (IOVIS BIOMEDICAL AND PHARMACEUTICAL CONSULTANTS) relates to phenyl ethanol amine ethers acting as beta adrenergic agonists that may be applied topically to skin.
Notably, none of the above-mentioned patents and patent applications disclose topically administrable compositions, wherein the beta2-adrenoceptor agonist is the primary therapeutical agent or the sole therapeutical agent.